Closed since over 6 years ago
Intermediate Overall DesignDesign a protein that binds IL-7R!
Interleukin 7 receptor (IL-7R) is a protein that helps regulate the human immune system, and is an important target in cancer therapy research. In this puzzle, players start with two frozen helices bound to the IL-7R target (also frozen). Players can fold and design about 20 residues between the binding helices, with the goal of creating a well-folded protein that can bind the IL-7R target! Players may also redesign residues on the backside of the binding helices, but residues at the IL-7R interface are frozen in place. The most promising designs will have lots of helical and sheet structure with only short loops, and will have a well-packed, buried core. There are several Objectives in place; see the puzzle comments for details.
This is the 14th puzzle in the IL-7R binder series, meant to generate a large diversity of designs that can be tested in a high-throughput binding experiment! The binding helices in this puzzle are the same as in Round 13, but with with the designable region between the helices instead of at their termini. Due to time constraints, puzzles in this series will be online for only 4 days at a time. See the blog for more information. Remember, you can use the Upload for Scientists button for up to 5 designs that you want us to look at, even if they are not the best-scoring solutions!
100 pts.
11,278
Residue IE Score (max +500)
Monitors that all PHE, TYR, and TRP residues are scoring well.
Core Existence (max +1000)
Ensures that at least 25% of residues are buried in the protein core.
SS Design (max +300)
Penalizes all CYS residues. Penalizes GLY, ALA, SER, THR in helices. Penalizes GLY, ALA in sheets.
Residue Count (max +100)
Penalizes extra residues inserted beyond 110, at a cost of 20 points per residue. Players may use up to 115 residues in total.
How about making the connecting loops (68,93) either longer or just flexible. It would prevent the tendency of the folds to be pulled backward into an orthogonal relationship with the frozen helices.
I'm not sure I know what you mean—can you elaborate a bit more? Do you have a solution or screenshot to help illustrate a fold that is "pulled backward into an orthogonal relationship"?
The current setup is intended to give Foldit players the most freedom. The frozen helices (including segments 68 and 93) are the minimum portion required for binding, and the two cutpoints should allow players to do whatever they want with the remaining designable portion.
We could insert a non-frozen region at the connection (e.g. between segment 68 and the cutpoint). But players would be limited in the ways they could manipulate this region, since it would be tethered to the frozen region; and in theory you should be able to reach the same solutions with the current setup (where the frozen portion ends immediately in a cutpoint).
If you're feeling constrained by the current setup, it could be that there's a bug or that some tools are not behaving properly with the cutpoints?
I'll try. It seems to me that the 2 cut-points mentioned are not allowing us to do what we want, easily. No matter what AAs we chose for the adjacent residues our fold, when I wiggle at a CI greater than say 0.10, rotates away from the frozen helices toward a 90 degree angle and even beyond. This happens even though the fold is banded to the frozen helices, and is also not merely repulsion between segments because this continues as mentioned way too far to 90 or plus degrees. The usual solution I find is to add one or two loop segments to my mutated fold in order to be freer from the aforementioned cuts. This means that I now have too long a loop and this is not a desirable outcome. Hope this makes it clearer. (Note: the good folders may not have this issue, so it just be my ignorance).
